title: Subchronic exposure to ethyl tertiary butyl ether resulting in genetic damage in Aldh2 knockout mice.
abstract: Ethyl tertiary butyl ether (ETBE) is biofuel additive recently used in Japan and some other countries. Limited evidence shows that ETBE has low toxicity. Acetaldehyde (AA), however, as one primary metabolite of ETBE, is clearly genotoxic and has been considered to be a potential carcinogen. The aim of this study was to evaluate the effects of ALDH2 gene on ETBE-induced genotoxicity and metabolism of its metabolites after inhalation exposure to ETBE. A group of wild-type (WT) and Aldh2 knockout (KO) C57BL/6 mice were exposed to 500ppm ETBE for 1-6h, and the blood concentrations of ETBE metabolites, including AA, tert-butyl alcohol and 2-methyl-1,2-propanediol, were measured. Another group of mice of WT and KO were exposed to 0, 500, 1750, or 5000ppm ETBE for 6h/day with 5 days per weeks for 13 weeks. Genotoxic effects of ETBE in these mice were measured by the alkaline comet assay, 8-hydroxyguanine DNA-glycosylase modified comet assay and micronucleus test. With short-term exposure to ETBE, the blood concentrations of all the three metabolites in KO mice were significantly higher than the corresponding concentrations of those in WT mice of both sexes. After subchronic exposure to ETBE, there was significant increase in DNA damage in a dose-dependent manner in KO male mice, while only 5000ppm exposure significantly increased DNA damage in male WT mice. Overall, there was a significant sex difference in genetic damage in both genetic types of mice. These results showed that ALDH2 is involved in the detoxification of ETBE and lack of enzyme activity may greatly increase the sensitivity to the genotoxic effects of ETBE, and male mice were more sensitive than females.
authors.affiliation: Japan National Institute of Occupational Safety and Health, Kawasaki, Japan.
authors.forename: Zuquan
authors.initials: Z
authors.lastname: Weng
authors.forename: Megumi
authors.initials: M
authors.lastname: Suda
authors.forename: Katsumi
authors.initials: K
authors.lastname: Ohtani
authors.forename: Nan
authors.initials: N
authors.lastname: Mei
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Tamie
authors.initials: T
authors.lastname: Nakajima
authors.forename: Rui-Sheng
authors.initials: RS
authors.lastname: Wang
mesh_terms: D000079:Acetaldehyde / Q000097:blood; D000280:Administration, Inhalation; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D020552:Comet Assay; D004249:DNA Damage; D005019:Ethyl Ethers / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015162:Micronucleus Tests; D011409:Propylene Glycols / Q000097:blood; D012737:Sex Factors; D059550:Toxicity Tests, Subchronic; D020002:tert-Butyl Alcohol / Q000097:blood
chemical_list: C583354:2-methyl-1,2-propandiol; D005019:Ethyl Ethers; D011409:Propylene Glycols; C098546:ethyl tert-butyl ether; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000079:Acetaldehyde; D020002:tert-Butyl Alcohol
keywords: 2-methyl-1,2-propanediol; 8-hydroxyguanine DNA-glycosylase; AA; ALDH2; Aldh2; ETBE; Ethyl tertiary butyl ether; Genetic damage; IARC; International Agency for Research on Cancer; KO; Kinetics; Knockout mice; MN-NCE; MN-RETs; MPD; MTBE; TBA; WT; acetaldehyde; aldehyde dehydrogenase2; ethyl tertiary butyl ether; hOGG1; knockout; methyl tertiary butyl ether; micronucleated reticulocytes; micronuclei in the mature normochromatic erythrocyte; tert-butyl alcohol; wild-type